Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes

Nat Commun. 2021 May 10;12(1):2579. doi: 10.1038/s41467-021-22338-2.

Abstract

Serum concentration of hepatic enzymes are linked to liver dysfunction, metabolic and cardiovascular diseases. We perform genetic analysis on serum levels of alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) using data on 437,438 UK Biobank participants. Replication in 315,572 individuals from European descent from the Million Veteran Program, Rotterdam Study and Lifeline study confirms 517 liver enzyme SNPs. Genetic risk score analysis using the identified SNPs is strongly associated with serum activity of liver enzymes in two independent European descent studies (The Airwave Health Monitoring study and the Northern Finland Birth Cohort 1966). Gene-set enrichment analysis using the identified SNPs highlights involvement in liver development and function, lipid metabolism, insulin resistance, and vascular formation. Mendelian randomization analysis shows association of liver enzyme variants with coronary heart disease and ischemic stroke. Genetic risk score for elevated serum activity of liver enzymes is associated with higher fat percentage of body, trunk, and liver and body mass index. Our study highlights the role of molecular pathways regulated by the liver in metabolic disorders and cardiovascular disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aged
  • Alanine Transaminase / blood
  • Alanine Transaminase / genetics*
  • Alkaline Phosphatase / blood
  • Alkaline Phosphatase / genetics*
  • Cardiovascular Diseases / enzymology
  • Cardiovascular Diseases / genetics*
  • Cohort Studies
  • Databases, Genetic
  • Female
  • Gene Expression Regulation, Enzymologic / genetics
  • Genetic Predisposition to Disease
  • Genetic Testing
  • Genome-Wide Association Study
  • Humans
  • Insulin Resistance / genetics
  • Lipid Metabolism / genetics
  • Liver / enzymology*
  • Liver / metabolism
  • Male
  • Mendelian Randomization Analysis
  • Metabolic Diseases / enzymology
  • Metabolic Diseases / genetics*
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Whites
  • gamma-Glutamyltransferase / blood
  • gamma-Glutamyltransferase / genetics*

Substances

  • gamma-Glutamyltransferase
  • Alanine Transaminase
  • Alkaline Phosphatase